Much effort has been expended to understanding the mechanisms of lung inflammation and injury of lung vascular and alveolar epithelial barriers, the hallmarks of the acute lung injury (ALI) syndrome. However, the primary approach to treatment of these patients remains optimizing the mechanical ventilation and administering antibiotics. Attempts to treat ALI with drugs and cell-based therapies have thus far been unsuccessful. The central research focus of this renewal application for years 11 to 15 will be on defining the resolution phase of inflammatory lung injury and approaches that activate the intrinsic resolution pathways and promote tolerance to injury occurring as a consequence of secondary infection. The innovative hypotheses outlined in each project will define the pro-resolution pathways in macrophages at the molecular and signaling levels. In Project 1, Dr. Asrar Malik, PI, will test the fundamental hypothesis that macrophage phagosomal acidification is regulated through the activation of the cation channel TRPM2 in the phagosomal membrane. Studies will be carried out to determine the function of TRPM2 in regulating the pH in phagosomes and determine its role in promoting resolution and generating tolerance. In Project 2, Dr. Dolly Mehta, PI, will test the hypothesis that a subpopulation of macrophages capable of generating sphingosine-1-phosphate are induced during the resolution phase, are essential for tissue repair, and have the capacity to induce tolerance. In Project 3, Dr. YouYang Zhao, PI, will test the hypothesis that Jag1 expressed in ECs through binding to Notch receptors in macrophages skews lung macrophages towards the pro-inflammatory M1-like phenotype whereas inhibiting Jag1 has the potential to re-program macrophages towards pro-resolving cells that promote the resolution of inflammatory lung injury and enhance the lung's tolerance to injury induced by secondary infection. This concerted effort using novel and rigorous approaches described in each project of the Program will lead to a new overall understanding of the signaling mechanisms responsible for resolving lung inflammatory injury, and potential therapeutic strategies to accelerate and enhance the pro-resolution mechanisms and increase the resilience of lungs.